Kinetic modelling of dissolution dynamic nuclear polarisation C magnetic resonance spectroscopy data for analysis of pyruvate delivery and fate in tumours.

Dissolution dynamic nuclear polarisation (dDNP) of C-labelled pyruvate in magnetic resonance spectroscopy/imaging (MRS/MRSI) has the potential for monitoring tumour progression and treatment response. Pyruvate delivery, its metabolism to lactate and efflux were investigated in rat P22 sarcomas following simultaneous intravenous administration of hyperpolarised C-labelled pyruvate ( C -pyruvate) and urea ( C-urea), a nonmetabolised marker. A general mathematical model of pyruvate-lactate exchange, incorporating an arterial input function (AIF), enabled the losses of pyruvate and lactate from tumour to be estimated, in addition to the clearance rate of pyruvate signal from blood into tumour, K , and the forward and reverse fractional rate constants for pyruvate-lactate signal exchange, k and k .

Quantitative Estimation of Tissue Blood Flow Rate.

The rate of blood flow through a tissue (F) is a critical parameter for assessing the functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind the estimation of F, how F relates to other commonly used measures of tissue perfusion, and a practical approach for estimating F in laboratory animals, using small readily diffusible and metabolically inert radio-tracers. The methods described require relatively nonspecialized equipment.

Human Kinetic Modeling of the 5HT6 PET Radioligand 11C-GSK215083 and Its Utility for Determining Occupancy at Both 5HT6 and 5HT2A Receptors by SB742457 as a Potential Therapeutic Mechanism of Action in Alzheimer Disease.

Unlabelled: Antagonism of 5-hydroxytrypamine-6 (5HT6) receptors is associated with procognitive effects in preclinical species, suggesting a therapeutic potential for this mechanism in Alzheimer disease (AD) and other cognitive diseases. In a phase 2 dose study, SB742457, a novel 5HT6 antagonist, showed increasing procognitive effects in patients with AD as the dose increased, with a procognitive signal in AD patients at a dose of 35 mg/d superior to the other doses tested (5 and 15 mg/d).

Methods: In this article, we describe the quantification and pharmacologic selectivity of a new 5HT6 PET ligand ((11)C-GSK215083) in healthy volunteers and its use to measure occupancies achieved at various doses of SB742457.

An evaluation of the brain distribution of [(11)C]GSK1034702, a muscarinic-1 (M 1) positive allosteric modulator in the living human brain using positron emission tomography.

Background: The ability to quantify the capacity of a central nervous system (CNS) drug to cross the human blood-brain barrier (BBB) provides valuable information for de-risking drug development of new molecules. Here, we present a study, where a suitable positron emission tomography (PET) ligand was not available for the evaluation of a potent muscarinic acetylcholine receptor type-1 (M1) allosteric agonist (GSK1034702) in the primate and human brain. Hence, direct radiolabelling of the novel molecule was performed and PET measurements were obtained and combined with in vitro equilibrium dialysis assays to enable assessment of BBB transport and estimation of the free brain concentration of GSK1034702 in vivo.

Acute increases in synaptic GABA detectable in the living human brain: a [¹¹C]Ro15-4513 PET study.

The inhibitory γ-aminobutyric acid (GABA) neurotransmitter system is associated with the regulation of normal cognitive functions and dysregulation has been reported in a number of neuropsychiatric disorders including anxiety disorders, schizophrenia and addictions. Investigating the role of GABA in both health and disease has been constrained by difficulties in measuring acute changes in synaptic GABA using neurochemical imaging. The aim of this study was to investigate whether acute increases in synaptic GABA are detectable in the living human brain using the inverse agonist GABA-benzodiazepine receptor (GABA-BZR) positron emission tomography (PET) tracer, [(11)C]Ro15-4513.

Non linear mixed effects analysis in PET PK-receptor occupancy studies.

The characterisation of a pharmacokinetic-receptor occupancy (PK-RO) relationship derived from a PET study is typically modelled in a conventional non-linear least squares (NLLS) framework. In the present work, we explore the application of a non-linear mixed effects approach (NLME) and compare this with NLLS estimation (using both naive pooled data and two-stage approaches) in the context of a direct PK-RO relationship described by an Emax model, using simulated data sets. Target and reference tissue time-activity curves were simulated using a two-tissue compartmental model and an arterial plasma input function for a typical PET study (12 subjects in 3 dose groups with 3 scans each).

Recommendations for measurement of tumour vascularity with positron emission tomography in early phase clinical trials.

The evaluation of drug pharmacodynamics and early tumour response are integral to current clinical trials of novel cancer therapeutics to explain or predict long term clinical benefit or to confirm dose selection. Tumour vascularity assessment by positron emission tomography could be viewed as a generic pharmacodynamic endpoint or tool for monitoring response to treatment. This review discusses methods for semi-quantitative and quantitative assessment of tumour vascularity.

Radiosynthesis and characterization of 11C-GSK215083 as a PET radioligand for the 5-HT6 receptor.

Unlabelled: The development of a PET radioligand for imaging 5-hydroxytryptamine (5-HT) 6 receptors in the brain would, for the first time, enable in vivo imaging of this target along with assessment of its involvement in disease pathophysiology. In addition, such a tool would assist in the development of novel drugs targeting the 5-HT6 receptor.

Methods: On the basis of in vitro data, GSK215083 was identified as a promising 5-HT6 radioligand candidate and was radiolabeled with (11)C via methylation.

A pharmacokinetic PET study of NK₁ receptor occupancy.

Purpose: There is growing recognition of the importance of integrating drug occupancy data acquired by positron emission tomography (PET) with the plasma pharmacokinetics of the drug, in order to establish proper dose selection in subsequent clinical trials. Here we present a study in human subjects of the occupancy of NK(1) receptors achieved following different doses of casopitant, a selective NK(1) antagonist.

Methods: Two PET scans were carried out in each of eight human subjects, with the PET radioligand [(11)C]GR205171, a high-affinity and selective NK(1) receptor antagonist.

Laser optoacoustic spectroscopy of gold nanorods within a highly scattering medium.

We describe a spectroscopic comparative analysis based on the optoacoustic technique over the wavelength range from 410nm to 1000nm using a Q-switched Nd:YAG pumped optical parametric oscillator tunable source on a gold nanostructure solution located within a highly scattering medium. The advantages of this method over standard spectroscopy techniques are the possibility to localize and monitor the spectroscopic response of absorbing materials located within turbid media. The operation is confirmed using a comparative analysis with the spectroscopic results obtained from a reference measurement scheme, based on a highly sensitive collimated optical transmission setup in parallel and under the same experimental conditions as the optoacoustic technique.

Prediction of repeat-dose occupancy from single-dose data: characterisation of the relationship between plasma pharmacokinetics and brain target occupancy.

Positron emission tomography (PET) is used in drug development to assist dose selection and to establish the relationship between blood and tissue pharmacokinetics (PKs). We present a new biomathematical approach that allows prediction of repeat-dose (RD) brain target occupancy (TO) using occupancy data obtained after administration of a single dose (SD). A PET study incorporating a sequential adaptive design was conducted in 10 healthy male adults who underwent 4 PET scans with [(11)C]DASB ([(11)C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine): 1 at baseline, 2 after 20 mg SD of the 5-hydroxytryptamine transporter (5-HTT) inhibitor duloxetine, and 1 after 4 days daily administration of 20 mg duloxetine.

A multi-center randomized proof-of-concept clinical trial applying [¹⁸F]FDG-PET for evaluation of metabolic therapy with rosiglitazone XR in mild to moderate Alzheimer's disease.

Here we report the first multi-center clinical trial in Alzheimer's disease (AD) using fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) measures of brain glucose metabolism as the primary outcome. We contrasted effects of 12 months treatment with the PPARγ agonist Rosiglitazone XR versus placebo in 80 mild to moderate AD patients. Secondary objectives included testing for reduction in the progression of brain atrophy and improvement in cognition.

Evaluation of 11C-GSK189254 as a novel radioligand for the H3 receptor in humans using PET.

Unlabelled: The histamine H(3) receptor is implicated in the pathophysiology of several central nervous system disorders. N-methyl-6-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)-nicotamide (GSK189254) is a highly potent, selective, and brain-penetrant H(3) receptor antagonist. Previous studies in the pig using PET have shown that (11)C-GSK189254 uptake in H(3)-rich regions of the brain can be blocked by the selective H(3) antagonist ciproxifan.

Simplified quantification of 5-HT2A receptors in the human brain with [11C]MDL 100,907 PET and non-invasive kinetic analyses.

Background: [(11)C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT(2A) receptor quantification in vivo. Studies suggest that [(11)C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses.

11C-GSK189254: a selective radioligand for in vivo central nervous system imaging of histamine H3 receptors by PET.

Unlabelled: The histamine H(3) receptor is a G-protein-coupled presynaptic auto- and heteroreceptor whose activation leads to a decrease in the release of several neurotransmitters including histamine, acetycholine, noradrenaline, and dopamine. H(3) receptor antagonists such as 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) can increase the release of these neurotransmitters and thus may offer potential therapeutic benefits in diseases characterized by disturbances of neurotransmission. The aim of this study was to synthesize and evaluate (11)C-labeled GSK189254 ((11)C-GSK189254) for imaging the histamine H(3) receptor in vivo by PET.

Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited.

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution (V(T)) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand (V(ND)) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available.

Quantitative estimation of tissue blood flow rate.

Tissue blood flow rate (F) is a critical parameter for assessing functional efficiency of a blood vessel network following angiogenesis. This chapter aims to provide the principles behind estimation of F and a practical approach to its determination in laboratory animals using small, readily diffusible, and metabolically inert radiotracers. The methods described require relatively nonspecialized equipment.

Gray matter blood flow change is unevenly distributed during moderate isocapnic hypoxia in humans.

Hypoxia increases cerebral blood flow (CBF), but it is unknown whether this increase is uniform across all brain regions. We used H(2)(15)O positron emission tomography imaging to measure absolute blood flow in 50 regions of interest across the human brain (n = 5) during normoxia and moderate hypoxia. Pco(2) was kept constant ( approximately 44 Torr) throughout the study to avoid decreases in CBF associated with the hypocapnia that normally occurs with hypoxia.

Estimation of apparent tumor vascular permeability from multiphoton fluorescence microscopic images of P22 rat sarcomas in vivo.

Objective: To develop an image processing-based method to quantify the rate of extravasation of fluorescent contrast agents from tumor microvessels, and to investigate the effect of the tumor vascular disrupting agent combretastatin A-4-P (CA-4-P) on apparent tumor vascular permeability to 40 kDa fluorescein isothiocyanate (FITC) labeled dextran.

Methods: Extravasation of FITC-dextran was imaged in 3 dimensions over time within P22 sarcomas growing in dorsal skin flap "window chambers" in BDIX rats using multiphoton fluorescence microscopy. Image processing techniques were used to segment the data into intra- and extravascular regions or classes.

Consensus nomenclature for in vivo imaging of reversibly binding radioligands.

An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

Characterization of the SPECT 5-HT2A receptor ligand 123I-R91150 in healthy volunteers: part 2--ketanserin displacement.

Unlabelled: As part of the radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) characterization study, ketanserin challenges were performed on healthy volunteers with the aim of assessing the specificity of (123)I-R91150 binding to subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), the sensitivity of (123)I-R91150 SPECT in measuring ligand displacement, the relationship between ketanserin plasma concentrations and (123)I-R91150 displacement, and the suitability of the cerebellum as a reference region for quantification.

Methods: Dynamic SPECT was performed on 6 healthy men (mean age +/- SD, 21 +/- 0.89 y) from the time of (123)I-R91150 injection until 470 min afterward.

Characterization of the SPECT 5-HT2A receptor ligand 123I-R91150 in healthy volunteers: Part 1--pseudoequilibrium interval and quantification methods.

Unlabelled: With the aim of characterizing radioiodinated 4-amino-N-1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) as a SPECT ligand for subtype 2A of the 5-hydroxytryptamine receptor (5-HT(2A)), tracer kinetic compartmental analyses were compared with the tissue ratio method (TR). The pseudoequilibrium interval after a single bolus injection was identified, and a reference database of specific uptake ratio (SUR) values was obtained. Within-scan and between-subject variability was also assessed.

Validation of a tracer kinetic model for the quantification of 5-HT(2A) receptors in human brain with [(11)C]MDL 100,907.

The positron emission tomography (PET) ligand [(11)C]MDL 100,907 has previously been introduced to image the serotonin 2A (5-HT(2A)) receptor in human brain. The aim of this work was to contribute to the verification of the tracer kinetic modelling in human studies. Five healthy volunteers were scanned twice after intravenous bolus injection of approximately 370 MBq [(11)C]MDL 100,907 using dynamic PET.

Behaviour of [11C]R(-)- and [11C]S(+)-rolipram in vitro and in vivo, and their use as PET radiotracers for the quantificative assay of PDE4.

Cyclic AMP (cAMP) is a continually produced nucleotide which is inactivated by hydrolysis to 5'AMP via phosphodiesterase 4 (PDE4) enzymes. Rolipram is a selective PDE4 inhibitor which exists in two enantiomeric forms, R(-) and S(+). Both of these enantiomers have previously been labelled with carbon-11 and used as positron emission tomography (PET) ligands for measuring PDE4 expression and function, and indirectly to explore the function of the cAMP second messenger, in vivo, using PET.